Angiographic Findings in Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) Trial Alexandra J. Lansky1, Ken Mori1, Ricardo A. Costa1, Michel Bertrand2, Frederick Feit3, Cordy Pietras1, Ecatarina Cristea1, Stuart Pocock4, Magnus Ohman5, Gregg W. Stone1 1. Cardiovascular Research Foundation, New York, NY; 2. Hospital Cardiologique, Lambersart, France 3. New York University Medical Center, NY 4. London School of Hygiene and Tropical Medicine, London, United Kingdom 5. University of North Carolina, Chapel Hill, NC

Background A number of angiographic morphologic parameters of prognostic importance have been identified in ACS pts undergoing PCI including the extent of disease, the presence of thrombus and coronary flow characteristics. ACUITY Angiographic substudy was designed to investigate the angiographic findings in a cohort of patients enrolled in US.

ACUITY Trial Design Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) UFH or Enoxaparin + GP IIb/IIIa Bivalirudin Alone R* Angiography within 72h Medical management PCI CABG Moderate- high risk ACS Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Major entry criteria Inclusion Criteria Exclusion Criteria Moderate-high risk unstable angina or NSTEMI Inclusion Criteria Age ≥18 years Chest pain ≥10’ within 24h At least one of: New ST depression or transient ST elevation ≥1 mm Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria Age ≥65 years Aspirin within 7 days ≥2 angina episodes w/i 24h ≥3 cardiac risk factors Written informed consent Exclusion Criteria No angiography within 72h Acute STEMI or shock Bleeding diathesis or major bleed within 2 weeks Platelet count ≤100,000/mm3 INR >1.5 control CrCl ≤30 ml/min Abcx or ≥2 prior LMWH doses Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed Allergy to drugs, contrast

ACUITY Primary Results (ITT) Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone PNI <0.001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PSup <0.001 *Heparin=unfractionated or enoxaparin

ACUITY: Angiographic Substudy Objectives: Investigate the angiographic basis of observed differences in efficacy of angiographic parameters in acute coronary syndrome patients. Methods: Angiographic films were analyzed in a blinded manner by the independent Core Laboratory: Baseline Angiography on all patients to assess the extent of disease Serial analysis of diseased vessels for patients undergoing PCI to determine procedural complications and final QCA results.

Consort Diagram

Baseline clinical characteristics UFH/Enoxaparin + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin alone (N=4,612) Age (median [range], yrs) 63 [23-91] 63 [21-95] 63 [20-92] Male 70.6% 69.9% 69.3% Diabetes 28.4% 27.7% 28.1% - Insulin requiring 8.5% 8.7% 8.9% Hypertension 66.8% 67.2% 67.1% Hyperlipidemia 57.2% 57.4% 57.0% Current smoker 29.0% 29.3% Prior MI 31.6% 30.5% 31.8% Prior PCI 39.0% 37.8% 39.9% Prior CABG 18.2% 17.4% 18.1% Renal insufficiency* 19.2% 19.1% 18.9% *CrCL < 60ml/min as determined by the Cockcroft-Gault equation

Baseline angiographic characteristics UFH+GPI N=2314 Biv+GPI N=2301 Bivalirudin N=2306 P value Lesions / pts 4.1 ± 2.9 4.1 ± 3.0 0.56 # of diseased vessel, % - 0VD 9.0 9.9 0.43 - 1VD 18.5 18.6 18.3 0.94 - 2VD 27.1 28.0 29.2 0.27 - 3VD 45.5 44.4 42.6 0.15 Extent of disease, mm 40.7 ± 30.8 39.8 ± 29.3 39.3 ± 30.2 Lesion Location, % - LAD 74.5 75.6 73.8 0.36 - RCA 69.5 69.0 66.6 0.08 - LCX 65.0 63.3 64.1 0.49 Diseased vessel is defied as %DS>30%

Baseline angiographic characteristics UFH+GPI N=2314 Biv+GPI N=2301 Bivalirudin N=2306 P value Jeopardy Score 2.4 ± 2.8 2.4 ± 2.7 2.3 ± 2.8 0.19 Ejection Fraction, % 63.7 ± 11.9 64.3 ± 12.7 64.6 ± 12.0 0.05 TIMI flow glade - 0/1 9.0 8.6 8.2 0.22 - 2 4.9 4.7 5.1 0.59 - 3 86.0 86.7 0.43 Myocardial Blush grade 8.8 8.4 0.67 12.3 12.7 12.9 0.63 79.1 78.4 78.7 0.69

LAD angiographic characteristics UFH+GPI N=2275 Biv+GPI N=2272 Bivalirudin N=2267 P value # of lesions 1.5 ± 1.3 0.99 Extent of diseases, mm 22.1 ± 16.6 20.9 ± 14.9 21.3 ± 15.7 0.57 Lesion Morphology, % Thrombus 5.8 4.7 5.7 0.17 Eccentric 8.4 8.2 0.97 Ulcerated 2.0 1.8 1.4 0.34 Aneurysm 1.7 1.1 0.06 Ectasia 3.3 3.2 0.96 Calcium - Moderate 18.5 19.9 20.0 0.36 - Severe 5.3 5.5 5.2 0.93 Diseased vessel is defied as %DS>30%

LAD angiographic characteristics UFH+GPI N=2275 Biv+GPI N=2272 Bivalirudin N=2267 P value TIMI flow glade, % - 0/1 5.3 4.4 5.5 0.20 - 2 6.5 6.7 6.2 0.78 - 3 88.2 88.9 88.3 0.72 Myocardial Blush Score, % 5.7 5.8 6.1 0.83 13.0 13.1 14.1 0.55 81.3 81.1 79.8 0.42 Collaterals, % 7.5 7.0 7.7 0.66 Rentrop classification n=179 n=165 n=180 - 0 2.8 3.6 1.1 0.30 - 1 20.1 19.4 26.1 0.25 53.1 52.1 55.6 0.80 24.0 24.8 17.2 0.16

RCA angiographic characteristics UFH+GPI N=2231 Biv+GPI N=2227 Bivalirudin N=2221 P value # of lesions 1.5 ± 1.4 0.10 Extent of diseases, mm 23.1 ± 15.8 22.6 ± 16.7 22.8 ± 17.9 0.17 Lesion Morphology, % Thrombus 7.3 7.9 0.68 Eccentric 9.0 9.9 8.4 0.22 Ulcerated 2.9 3.2 2.6 0.42 Aneurysm 2.0 1.6 2.2 Ectasia 6.8 6.7 5.3 0.06 Calcium - Moderate 16.7 17.6 16.5 0.58 - Severe 3.9 4.5 4.4 Diseased vessel is defied as %DS>30%

RCA angiographic characteristics UFH+GPI N=2231 Biv+GPI N=2227 Bivalirudin N=2221 P value TIMI flow glade, % - 0/1 14.4 14.0 12.5 0.14 - 2 5.7 5.2 6.1 0.41 - 3 79.9 80.8 81.4 0.45 Myocardial Blush Score, % 11.6 13.1 11.5 0.23 12.4 14.1 13.4 0.27 76.0 72.8 75.0 0.06 Collaterals 17.7 16.8 15.8 Rentrop classification n=405 n=382 n=356 - 0 0.5 1.6 1.7 0.25 - 1 9.9 10.7 9.0 0.73 54.8 49.2 47.8 0.12 34.8 38.5 41.6 0.16

LCX angiographic characteristics UFH+GPI N=2268 Biv+GPI N=2261 Bivalirudin N=2264 P value # of lesions 1.2 ± 1.2 1.1 ± 1.2 0.58 Extent of diseases, mm 19.3 ± 14.5 18.9 ± 13.6 19.0 ± 13.7 0.95 Lesion Morphology, % Thrombus 4.6 5.2 5.6 0.33 Eccentric 5.4 6.1 5.8 0.61 Ulcerated 1.2 1.6 1.0 0.17 Aneurysm 1.1 0.32 Ectasia 3.3 2.9 3.4 Calcium - Moderate 13.2 13.5 12.8 0.76 - Severe 2.0 2.3 0.72 Diseased vessel is defied as %DS>30%

LCX angiographic characteristics UFH+GPI N=2268 Biv+GPI N=2261 Bivalirudin N=2264 P value TIMI flow glade, % - 0/1 7.5 7.3 6.6 0.50 - 2 2.6 2.3 3.0 0.28 - 3 90.0 90.4 90.3 0.88 Myocardial Blush Score, % 8.4 7.6 7.4 0.47 11.6 11.0 11.2 0.81 80.0 81.4 81.3 0.42 Collaterals 9.5 10.1 0.13 Rentrop classification n=225 n=227 n=200 - 0 2.2 4.5 - 1 18.2 20.7 18.0 0.72 54.7 56.8 49.5 0.30 24.9 20.3 28.0 0.17

PCI patients characteristics

Angiographic Characteristics UFH+GPI N=1616 Biv+GPI N=1680 Bivalirudin N=1617 P value Lesions / pts 4.3 ± 2.6 4.4 ± 2.7 0.86 # of diseased vessel, % 0.3 1.0 0.04 - 1VD 19.3 19.1 18.5 0.88 - 2VD 33.3 34.8 0.64 - 3VD 47.1 47.4 45.7 0.66 Extent of disease, mm 39.7 ± 27.1 39.2 ± 26.1 39.0 ± 26.6 0.90 Lesion Location, % - LAD 79.7 81.9 79.9 0.31 - RCA 77.2 76.1 73.7 0.12 - LCX 70.2 69.7 71.6 0.58 Jeopardy Score 2.6 ± 2.3 2.7 ± 2.3 0.29 Ejection fraction, % 63.4 ± 11.8 64.1 ± 12.5 64.1 ± 12.3 0.26 Women were older, more frequent DM, HT , current HL renal insufficiency.

PCI patients lesion characteristics UFH+GPI N=1616 Biv+GPI N=1680 Bivalirudin N=1617 P value Target Vessel, % - LAD 32.9 35.2 35.9 0.16 - RCA 36.4 34.6 31.5 0.01 - LCX 30.8 30.2 32.5 0.32 - SVG 7.0 8.0 8.6 0.23 - IMA 0.4 0.2 0.57 Lesion Length, mm 15.8 ± 10.2 15.6 ± 10.4 15.7 ± 10.2 0.60

PCI patients lesion characteristics UFH+GPI N=1616 Biv+GPI N=1680 Bivalirudin N=1617 P value Lesion Morphology, % Thrombus 14.2 14.6 15.9 0.32 Eccentric 20.2 21.7 20.9 0.61 Ulcerated 4.5 5.4 4.0 0.16 Aneurysm 1.2 1.3 1.5 0.78 Ectasia 5.9 6.0 5.5 0.77 Calcium - Moderate 21.9 21.5 20.4 0.58 - Severe 3.2 3.6 0.83 ACC/AHA B2/C 67.5 65.1 67.3 0.24

PCI patients lesion characteristics UFH+GPI N=1616 Biv+GPI N=1680 Bivalirudin N=1617 P value TIMI flow glade, % - 0/1 12.5 11.6 13.2 0.39 - 2 9.2 9.3 10.1 0.67 - 3 78.3 79.1 76.8 0.27 Myocardial Blush Score, % 16.1 14.2 16.3 0.23 14.7 15.1 17.1 0.18 69.2 70.7 66.6 0.06 Myocardial Blush Score (TIMI3 patients), % 1.6 2.5 2.1 0.30 14.9 14.3 16.8 83.5 83.2 81.1 0.28

Side branch UFH+GPI N=1616 Biv+GPI N=1680 Bivalirudin N=1617 P value Bifurcation lesion, % 18.9 18.8 0.99 Pre Procedure %DS 35.9 ± 30.9 35.0 ± 29.8 32.9 ± 28.7 0.63 50-75% 17.5 16.0 14.4 0.57 >75% 14.3 12.7 11.4 Worst SB %DS 59.9 ± 32.6 56.6 ± 32.0 60.5 ± 30.4 0.35 Post Procedure 41.0 ± 35.3 40.2 ± 34.5 43.7 ± 34.5 0.36 SB treated, % 26.0 22.2 21.9

QCA results UFH+GPI N=1616 Biv+GPI N=1680 Bivalirudin N=1617 P value Pre procedure RVD, mm 2.8 ± 0.6 0.85 MLD, mm 0.7 ± 0.5 0.91 %DS 73.5 ± 16.0 73.7 ± 15.5 72.5 ± 16.0 0.94 Lesion length, mm 15.8 ± 10.2 15.6 ± 10.4 15.7 ± 10.2 0.60 Post procedure In-segment 2.3 ± 0.6 0.88 17.7 ± 12.4 17.0 ± 11.4 16.8 ± 10.9 0.25 Acute gain 1.6 ± 0.6 0.82 In-stent 2.7 ± 0.5 8.2 ± 6.2 8.1 ± 5.1 8.3 ± 6.0 0.70

Conclusions The ACUITY trial demonstrated that a bivalirudin alone strategy results in a significantly improved net clinical outcome at 30 days when compared with heparin (unfractionated or enoxaparin) plus a GP IIb/IIIa inhibitor A further analysis of the baseline angiographic characteristics demonstrated that angiographic parameters were well-balanced between the treatment groups There were no clinically significant differences in the angiographic outcome of patients who underwent further PCI Despite being older and with more co-morbidities, women with AMI treated with primary stenting had similar early and late outcome compared to men. These favorable results may be related to the fact that women had similar time to reperfusion and smaller infract size compared to men. Discrepancy for the other previous reports might be due to no significant differences in diabetes rate and symptom onset to balloon time. In the EMERALD trial, despite women was older, had smaller BSA and comorbidites, women with AMI treated with primary PCI showed a similar early and late outcomes compared to men. This might be related that women had good ST-resolution and smaller infarct size compared to men. Prior CABG, infarct size and renal insufficiency were independence predictors of 6-month MACE after primary PCI. Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.